scholarly journals Resveratrol improves cardiac function and left ventricular fibrosis after myocardial infarction in rats by inhibiting NLRP3 inflammasome activity and the TGF-β1/SMAD2 signaling pathway

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e11501
Author(s):  
Jinjin Jiang ◽  
Xiuping Gu ◽  
Huifeng Wang ◽  
Shibin Ding
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Signaling Pathway ◽  
Rat Model ◽  
Nlrp3 Inflammasome ◽  
Interstitial Fibrosis ◽  
Left Ventricular ◽  
Sham Operation ◽  
Protective Effects ◽  
Inflammasome Activity

Background Several studies have shown that resveratrol (RES), a naturally occurring polyphenol found in many plants, is beneficial for preventing cardiovascular diseases. However, the mechanism underlying the RES-mediated protection against myocardial infarction has not yet been revealed entirely. In this study, we investigated the protective effects of RES on cardiac function in a rat model of acute myocardial infarction (AMI) and the related underlying mechanisms. Methods Male Sprague-Dawley rats were randomly divided into four groups: Sham (sham operation), Sham-RES, AMI (AMI induction), and AMI-RES. The rat AMI model was established by the permanent ligation of left anterior descending coronary artery method. The rats in the RES-treated groups were gavaged with RES (50 mg/kg/day) daily for 45 days after the Sham operation or AMI induction; rats in the Sham and AMI groups were gavaged with deionized water. Cardiac function was evaluated by echocardiography. Atrial interstitial fibrosis was assessed by hematoxylin-eosin or Masson’s trichrome staining. Real-time PCR and western blotting analyses were performed to examine the levels of signaling pathway components. Results RES supplementation decreased the inflammatory cytokine levels, improved the cardiac function, and ameliorated atrial interstitial fibrosis in the rats with AMI. Furthermore, RES supplementation inhibited NLRP3 inflammasome activity, decreased the TGF-β1 production, and downregulated the p-SMAD2/SMAD2 expression in the heart. Conclusion RES shows notable cardioprotective effects in a rat model of AMI; the possible mechanisms underlying these effects may involve the improvement of cardiac function and atrial interstitial fibrosis via the RES-mediated suppression of NLRP3 inflammasome activity and inhibition of the TGF-β1/SMAD2 signaling pathway in the heart.

scholarly journals Qiliqiangxin Attenuates Cardiac Remodeling via Inhibition of TGF-β1/Smad3 and NF-κB Signaling Pathways in a Rat Model of Myocardial Infarction

2018 ◽  
Vol 45 (5) ◽  
pp. 1797-1806 ◽  
Author(s):  
Anbang Han ◽  
Yingdong Lu ◽  
Qi Zheng ◽  
Jian Zhang ◽  
YiZhou Zhao ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Cardiac Function ◽  
Signaling Pathways ◽  
Rat Model ◽  
Cardiac Remodeling ◽  
Left Ventricular ◽  
Protective Effects ◽  
Tnf Α ◽  
Tgf Β1

Background/Aims: Qiliqiangxin (QL), a traditional Chinese medicine, has been demonstrated to be effective and safe for the treatment of chronic heart failure. Left ventricular (LV) remodeling causes depressed cardiac performance and is an independent determinant of morbidity and mortality after myocardial infarction (MI). Our previous studies have shown that QL exhibits cardiac protective effects against heart failure after MI. The objective of this study was to explore the effects of QL on myocardial fibrosis in rats with MI and to investigate the underlying mechanism of these effects. Methods: A rat model of acute myocardial infarction was induced by ligating the left anterior descending coronary artery. The rats were treated with QL (1.0 g/kg/day) for 4 weeks after surgery. Echocardiography and histology examination were performed to evaluate heart function and fibrosis, respectively. Protein levels of transforming growth factor-β1 (TGF-β1), phosphorylated Smad3 (p-Smad3), phosphorylated Smad7 (p-Smad7), collagen I (Col- I), alpha smooth muscle actin (a-SMA), tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), nuclear factor κB (NF-κB), and phosphorylated inhibitor of kappa B alpha (p-IκBα) were measured by western blot analysis. Results: QL treatment ameliorated adverse cardiac remodeling 8 weeks after AMI, including better preservation of cardiac function, decreased inflammation, and reduced fibrosis. In addition, QL treatment reduced Col-I, a-SMA, TGF-β1, and p-Smad3 expression levels but increased p-Smad7 levels in postmyocardial infarct rat hearts. QL administration also reduced the elevated levels of cardiac inflammation mediators, such as TNF-α and IL-6, as well as NF-κB and p-IκBα expression. Conclusions: QL therapy exerted protective effects against cardiac remodeling potentially by inhibiting TGF-β1/Smad3 and NF-κB signaling pathways, thereby preserving cardiac function, as well as reducing myocardial inflammation and fibrosis.

Abstract 13810: TT-00920, a Clinical Stage Novel Phosphodiesterase 9 Inhibitor, Protects Against Heart Failure in a Rat Model of Myocardial Infarction

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Zejuan Sheng ◽  
Xiaoyan Qiang ◽  
Guoyu Li ◽  
Huimin Wang ◽  
Wenxin Dong ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Cardiac Function ◽  
Rat Model ◽  
Cardiac Fibrosis ◽  
Clinical Stage ◽  
Left Ventricular ◽  
Guanosine Monophosphate ◽  
Therapeutic Effects ◽  
Dependent Manner

Introduction: Phosphodiesterase 9 (PDE9) controls natriuretic-peptide-stimulated cyclic guanosine monophosphate in cardiac myocytes and is stongly upregulated in human heart failure, suggesting its potential as a promising therapeutic target in heart failure. Here we investigated the potential effects of TT-00920, a clinical stage novel and highly selective PDE9 inhibitor, on heart failure in a rat model of myocardial infarction. Methods: Myocardial infarction was induced by left anterior descending coronary artery (LAD) ligation in male Sprague Dawley rats. After 4-week treatment of vehicle, LCZ696, TT-00920, or TT-00920/Valsartan by oral gavage, efficacy was assessed by echocardiography and cardiac histopathology. Results: TT-00920 had remarkably improved cardiac function, protected against cardiac remodeling and fibrosis in a dose-dependent manner. TT-00920/Valsartan combination showed superior beneficial efficacy when compared to TT-00920 or LCZ696 single agent.Figure 1. TT-00920 improved cardiac function and ventricular remodeling.Figure 2. TT-00920 attenuated cardiac fibrosis in peri-infarct zone. Conclusions: TT-00920 reversed LAD-induced left ventricular dysfunction and remodeling, supporting its potential as a novel therapeutic agent for heart failure. The superior efficacy of TT-00920/Valsartan combination suggests that TT-00920 and renin-angiotensin-aldosterone system inhibitors may have additive therapeutic effects in heart failure.TT-00920 is currently being evaluated in Phase 1 clinical study for safety, tolerability, pharmacokinetics and pharmacodynamics in healthy volunteers (NCT04364789).

scholarly journals Thyroid hormone mediates cardioprotection against postinfarction remodeling and dysfunction through the IGF-1/PI3K/AKT signaling pathway

2020 ◽  
Author(s):  
Bin Zeng ◽  
Xiaoting Liao ◽  
Lei Liu ◽  
Caixia Zhang ◽  
Huaiyu Ruan
Keyword(s):  
Myocardial Infarction ◽  
Cardiovascular Diseases ◽  
Thyroid Hormone ◽  
Signaling Pathway ◽  
Akt Signaling ◽  
Left Ventricular ◽  
Sham Operation ◽  
Akt Signaling Pathway ◽  
Anti Inflammatory ◽  
Related Proteins

Abstract Background Severe cardiovascular diseases, such as myocardial infarction or heart failure, can alter thyroid hormone (TH) secretion and peripheral conversion, leading to low triiodothyronine (T3) syndrome. Accumulating evidence suggests that TH has protective properties against cardiovascular diseases and that treatment with TH can effectively reduce myocardial damage after myocardial infarction (MI). However, the potential mechanisms are not clear. This study was designed to investigate the effect of T3 pretreatment on cardiac function and pathological changes in mice subjected to MI and the underlying mechanisms. Methods Adult male C57BL/6 mice underwent surgical ligation of the left anterior descending coronary artery (LAD) (or sham operation) to establish a myocardial infarction model. T3, BMS-754807 (inhibitor of insulin-like growth factor-1 receptor (IGF-1R)) or vehicle was administered before surgery. Results Compared with the MI group, the T3 pretreatment group exhibited significant attenuation of the myocardial infarct area, inhibition of cardiomyocyte apoptosis and fibrosis, and improved left ventricular function after MI. In addition, T3 exhibited an enhanced potency to stimulate angiogenesis and exert anti-inflammatory effects by reducing the levels of serum inflammatory cytokines after myocardial infarction. However, all of these protective effects were inhibited by the IGF-1R inhibitor BMS-754807. Moreover, the protein expression of IGF-1/PI3K/AKT signaling-related proteins, such as IGF-1, IGF-1R, phosphorylated PI3K (p-PI3K) and p-AKT was significantly upregulated in MI mice that received T3 pretreatment, and BMS-754807 pretreatment blocked the upregulation of the expression of these signaling-related proteins. Conclusion T3 pretreatment can protect the heart against dysfunction post-MI through its anti-apoptotic, anti-fibrotic, anti-inflammatory and angiogenesis-stimulating effects, which may be mediated by the activation of the IGF-1/PI3K/AKT signaling pathway.

Abstract 16459: Myocardial Replenishment of Tissue Inhibitor of Metalloproteinase (TIMP)-3 and TIMP4 Following Myocardial Infarction Result in Differential Protective Effects

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Abhijit Takawale ◽  
Ratnadeep Basu ◽  
Xiuhua Wang ◽  
Zamaneh Kassiri
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Cellular Response ◽  
Imaging System ◽  
Tissue Injury ◽  
Left Ventricular ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Protective Effects ◽  
Beneficial Effects ◽  
Adverse Remodeling

Introduction: The cardiomyopathy ensuing myocardial infarction (MI) results from the ischemic loss of the myocardium, impaired left ventricular (LV) dilation, eventually leading to heart failure. This is accompanied with adverse remodeling of the extracellular matrix (ECM) and disrupted balance of its regulatory proteins, particularly TIMP3 and TIMP4 that are reduced shortly after MI induction. Hypothesis: Replenishment of TIMP3 and/or TIMP4 post-MI will hinder adverse remodeling of the ECM and may also promote beneficial cellular response to limit tissue injury and cardiac dysfunction. Methods: MI was induced in adult male wildtype (C57BL/6) mice by ligation of the left anterior descending artery. Adenoviral constructs expressing human TIMP3 (Ad-hTIMP3), human TIMP4 (Ad-hTIMP4) or no-TIMP control (Ad-Null) were injected in the peri-infarct zone (5 injections/heart; 5.4x107 pfu/heart). Cardiac function was assessed by Vevo2100 ultrasound imaging system. Cellular and molecular analyses (inflammation, cell viability, angiogenesis, ECM composition) were assessed at 3 and 7 days post-MI. Results: Injection of Ad-Null had minimal effects in the post-MI dysfunction and remodeling. Ad-hTIMP3 injection exerted more beneficial effects compared to Ad-hTIMP4. Ad-TIMP3 group showed significantly better cardiac function (EF=35.49±2.52%, p<0.05), and to a lesser extent Ad-TIMP4 group (EF=28.79±1.79%) compared to Ad-Null group (EF=25.46±2.29%). Similarly, LV dilation was markedly attenuated in Ad-TIMP3 (LVEDV=77.08±6.05μL) but not in Ad-TIMP4 group (LVED=112.98±5.68 μL) compared to Ad-Null (LVEDV=112.98±7.0 μL). Inflammatory response (macrophage/neutrophil density) was not altered with Ad-TIMP treatment. Interestingly, the infarct size was smaller in Ad-TIMP3 group and even after 1wk post-MI, viable myocytes were detected in these hearts. Assessment of coronary density in the infarct and peri-infarct regions (intra-jugular fluoro-tagged lectin injection) revealed that Ad-TIMP3 promoted angiogenesis in the infarcted myocardium. Conclusions: This novel pro-angiogenic function of TIMP3 post-MI, in addition to its MMP inhibitory function, could provide additional beneficial effects in post-MI treatment.

Estradiol valerate enhances cardiac function via the Nrf2 signaling pathway to protect against oxidative stress by the Nrf2 signaling pathway in an ovariectomized rat model

2021 ◽  
Vol 27 ◽  
Author(s):  
Xin Qian ◽  
Jiao Wang ◽  
Minghui Cai ◽  
Haijuan Sun ◽  
Han Xu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cardiac Function ◽  
Signaling Pathway ◽  
Left Ventricular ◽  
Estradiol Valerate ◽  
Sham Operation ◽  
Antioxidant Genes ◽  
Bilateral Ovariectomy ◽  
Increased Risk ◽  
Nrf2 Signaling Pathway

Background: The increased risk of cardiovascular disease (CVD) in postmenopausal women and ovariectomized patients suggests that estrogen has a protective effect on cardiac function. Oxidative stress is the main cause of CVD, and the cellular defensive Nrf2 antioxidant pathway plays a protective role in various pathologies. However, the regulation of Nrf2 by estrogen has received little attention. Objective: The present study aimed to investigate the role of Nrf2 in the effect of estrogen on the cardiac function. Method:: In the present study, female SD rats were divided into three groups as follows: sham operation (SHAM), bilateral ovariectomy (OVX) and bilateral ovariectomy with estradiol valerate (EV) supplementation (OVX+EV). Vaginal smears and E2 concentrations were used to confirm model success. We compared cardiac morphology and function by echocardiography and HE staining. The levels of oxidative stress markers and antioxidant enzymes as well as protein expression of antioxidant genes were evaluated by Western blotting and immunohistochemistry. Results: Our results showed that supplementation with estrogen restored the parameters to some extent. Left ventricular end diastolic diameter at diastolic （LVID;d） and left ventricular volume at diastolic (LV vol;d) increased but MV E wave/A wave (E/A) significantly decreased. The oxidative stress indicators (malondialdehyde) increased, and the antioxidant activity indicators, such as superoxide dismutase (SOD) and catalase (CAT), decreased. Further, the expression of most Nrf2 antioxidant pathway-related proteins in the heart decreased after ovariectomy. Conclusion: The present study demonstrated that estrogen may protect cardiac function by regulating antioxidant capacity through the Nrf2 pathway.

Protective Effects of Allicin on ISO-Induced Rat Model of Myocardial Infarction via JNK Signaling Pathway

Pharmacology ◽  
2020 ◽  
Vol 105 (9-10) ◽  
pp. 505-513
Author(s):  
Wen Xu ◽  
Xiang-peng Li ◽  
En-ze Li ◽  
Yue-fen Liu ◽  
Jun Zhao ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Signaling Pathway ◽  
Rat Model ◽  
Dose Group ◽  
Sham Group ◽  
High Dose ◽  
Protective Effects ◽  
Jnk Signaling ◽  
T Wave ◽  
Jnk Signaling Pathway

<b><i>Objective:</i></b> This research was aimed to explore protective effects of allicin on rat model of myocardial infarction via JNK signaling pathway. <b><i>Methods:</i></b> Rat myocardial ischemia model was established with subcutaneous injection of isoproterenol (ISO). Seventy-five rats were randomly divided into 5 groups (<i>n</i> = 15): sham group, ISO group, low-dose group (1.2 mg/kg/days for 7 days), medium-dose group (1.8 mg/kg/days for 7 days), and high-dose group (3.6 mg/kg/days for 7 days). Routine HE staining and Masson staining were performed to observe myocardial histopathology. The expression of oxidative stress-related indicators, heart tissue apoptosis-related proteins, and JNK and p-JNK proteins were measured for different groups. <b><i>Results:</i></b> Compared with the sham group, the T wave value of the ISO group was significantly increased (<i>p &#x3c;</i> 0.01). When allicin was administered, the T wave values at different time points in all groups were all decreased. Compared with the sham group, the ratio of eNOS, Bcl-2/Bax was significantly decreased, and p-eNOS, iNOS, caspase-3, caspase-9, and Cyt-c were significantly elevated in the ISO group (<i>p &#x3c;</i> 0.05). After allicin was administered, significant changes in these proteins were observed in the medium- and high-dose groups. There was no significant change in the expression of JNK protein in the ISO group compared with the sham group; however, the expression of eNOS and p-JNK protein were significantly upregulated (<i>p &#x3c;</i> 0.01) and the expression of p-eNOS and iNOS were significantly downregulated (<i>p &#x3c;</i> 0.01). When allicin was administered, expression of p-JNK protein was significantly downregulated. <b><i>Conclusion:</i></b> Allicin can reduce oxidative stress damage and cardiomyocyte apoptosis in rat model of myocardial infarction and can significantly regulate JNK signaling pathway.

Blockade of NF-κB improves cardiac function and survival after myocardial infarction

2006 ◽  
Vol 291 (3) ◽  
pp. H1337-H1344 ◽  
Author(s):  
Shunichi Kawano ◽  
Toru Kubota ◽  
Yoshiya Monden ◽  
Takaki Tsutsumi ◽  
Takahiro Inoue ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Cardiac Remodeling ◽  
Diastolic Pressure ◽  
Interstitial Fibrosis ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Targeted Disruption ◽  
Ventricular Rupture ◽  
Inflammatory Processes

NF-κB is a key transcription factor that regulates inflammatory processes. In the present study, we tested the hypothesis that blockade of NF-κB ameliorates cardiac remodeling and failure after myocardial infarction (MI). Knockout mice with targeted disruption of the p50 subunit of NF-κB (KO) were used to block the activation of NF-κB. MI was induced by ligation of the left coronary artery in male KO and age-matched wild-type (WT) mice. NF-κB was activated in noninfarct as well as infarct myocardium in WT + MI mice, while the activity was completely abolished in KO mice. Blockade of NF-κB significantly reduced early ventricular rupture after MI and improved survival by ameliorating congestive heart failure. Echocardiographic and pressure measurements revealed that left ventricular fractional shortening and maximum rate of rise of left ventricular pressure were significantly increased and end-diastolic pressure was significantly decreased in KO + MI mice compared with WT + MI mice. Histological analysis demonstrated significant suppression of myocyte hypertrophy as well as interstitial fibrosis in the noninfarct myocardium of KO + MI mice. Blockade of NF-κB did not ameliorate expression of proinflammatory cytokines in infarct or noninfarct myocardium. In contrast, phosphorylation of c-Jun NH2-terminal kinase was almost completely abolished in KO + MI mice. The present study demonstrates that targeted disruption of the p50 subunit of NF-κB reduces ventricular rupture as well as improves cardiac function and survival after MI. Blockade of NF-κB might be a new therapeutic strategy to attenuate cardiac remodeling and failure after MI.

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